Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter NYU Cancer Center, NYU Langone Health, New York, NY, USA.
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Mol Cell. 2024 Aug 8;84(15):2807-2821. doi: 10.1016/j.molcel.2024.06.027. Epub 2024 Jul 17.
RAS proteins are conserved guanosine triphosphate (GTP) hydrolases (GTPases) that act as molecular binary switches and play vital roles in numerous cellular processes. Upon GTP binding, RAS GTPases adopt an active conformation and interact with specific proteins termed RAS effectors that contain a conserved ubiquitin-like domain, thereby facilitating downstream signaling. Over 50 effector proteins have been identified in the human proteome, and many have been studied as potential mediators of RAS-dependent signaling pathways. Biochemical and structural analyses have provided mechanistic insights into these effectors, and studies using model organisms have complemented our understanding of their role in physiology and disease. Yet, many critical aspects regarding the dynamics and biological function of RAS-effector complexes remain to be elucidated. In this review, we discuss the mechanisms and functions of known RAS effector proteins, provide structural perspectives on RAS-effector interactions, evaluate their significance in RAS-mediated signaling, and explore their potential as therapeutic targets.
RAS 蛋白是保守的鸟苷三磷酸（GTP）水解酶（GTPases），作为分子双稳态开关，在许多细胞过程中发挥着重要作用。当与 GTP 结合时，RAS GTPases 采用一种活性构象，并与特定的蛋白质相互作用，这些蛋白质被称为 RAS 效应物，它们含有保守的泛素样结构域，从而促进下游信号转导。在人类蛋白质组中已经鉴定出超过 50 种效应蛋白，其中许多已被研究为 RAS 依赖性信号通路的潜在介质。生化和结构分析为这些效应物提供了机制上的见解，使用模式生物的研究补充了我们对它们在生理和疾病中的作用的理解。然而，关于 RAS-效应物复合物的动力学和生物学功能的许多关键方面仍有待阐明。在这篇综述中，我们讨论了已知的 RAS 效应蛋白的机制和功能，提供了 RAS-效应物相互作用的结构视角，评估了它们在 RAS 介导的信号转导中的意义，并探讨了它们作为治疗靶点的潜力。
